Rats cause substantial damage each year to agricultural interests worldwide. The World Health Organization estimates that 20% of all human food is destroyed or contaminated by rodents each year (Chow, C. Y. The Biology and Control of the Norway Rat, Roof Rat and House Mouse, World Health. Organization, 1971). A recent US government report claims that each rat damages up to $10 worth of food and stored grains annually and contaminates five to 10 times that amount (Committee on Urban Pest Management, Urban Pest Management, National Academy Press: Washington D.C., 1980). With an estimated birth rate of 3.5 million per day globally, the estimated damage is valued at hundreds of millions of dollars per annum (Danoff, J. R. B. Introduced species summary reports, Centre of Research and Conservation, Columbia University, 2002).
In addition to this vast economic loss, rats are responsible for a number of health problems. By acting as vectors for both viral and bacterial diseases, rats transmit more than 35 types of disease to humans including leptospirosis, cholera, salmonella and the bubonic plague. Furthermore, rats are known to be one of the most invasive species responsible for a loss of biodiversity and native habitats, second only to humans. Rats threaten both plant and animal species by predation and habitat destruction.
Currently, a number of available toxicants are effective in controlling rats. Almost all are non-specific broad-spectrum rodenticides. To date, rodent control has been achieved through the use of sub-chronic poisons (e.g., cholecalciferol, bromethalin), acute poisons (e.g., zinc phosphide), first-generation anticoagulants (e.g., warfarin, coumatetralyl, diphacinone, chlorophacinone), and second-generation anticoagulants (e.g., brodifacoum, bromadiolone, bromethalin, difethialone, difenacoum), with varying degrees of success (Pelfrene, A. F. et al. Handbook of Pesticide Toxicology (Second Edition); Academic Press: San Diego, 2001, p 1793-1836). Annually, more than $500 million is spent on rodent control products. Second-generation anticoagulants are the most preferred products. However, most of these share a common disadvantage in that they associated with secondary non-target poisoning risks and are dangerous not only to children, but also to domestic pets, wildlife, and livestock.
Rodenticides rank second in the number of pesticide related poisonings recorded each year. A recent study revealed that just under 15,000 people were exposed to rodenticides in the US in 2008 alone, 86% being children under the age of six (Bronstein, A. C. et al. Clin. Toxicol. 2008, 46, 927-1057). In addition, rodenticides pose increasing risks to the environment and through the accumulation of residues in food chains. These poisons also suffer from a general lack of humaneness.
Norbormide (NRB) is a vasoactive also known under the trade names Shoxin® and Raticate® that was first introduced to the market as a rodenticide over thirty years ago. NRB was discovered in the 1960s and was found to be uniquely toxic to rats, but relatively harmless to other rodents and mammals (Roszkowski, A. P. et al. Science 1964, 144, 412-413). NRB displays unique species-specific constrictor activity that is restricted to the peripheral arteries of the rat. In arteries from all other species tested, as well as in rat aorta and extravascular smooth muscle tissue, NRB exhibits vasorelaxant properties at concentrations that induce vasoconstriction in the rat peripheral arteries (Bova, S. et al. Cardiovasc. Drug Rev. 2001, 19, 226-233).
Detailed studies conducted on the individual stereoisomers of NRB, isolated from the endo rich stereoisomeric mixture, found the parent compound's physiological effects to be strongly stereospecific. In rat peripheral arteries only the endo isomers of NRB retained the contractile activity elicited by the stereoisomeric mixture. Both the endo and exo isomers exhibit vasodilatory activity in rat aorta (Brimble, M. A. et al. Arkivoc 2004, 1-11). In vivo evaluation established that only the endo isomers of NRB were toxic in rats (Poos, G. I. et al. J. Med. Chem. 1966, 9, 537-540).
The mechanisms involved in the physiological divergent effects of NRB have not yet been clarified. Available evidence suggests that the vasoconstrictor effect may be mediated by the stimulation of a number of signal transduction pathways that lead to modulation of calcium influx, which is presumably mediated by phospholipase C (PLC)-coupled receptors expressed in rat peripheral artery myocytes (Bova, S. et al. J. Pharm. Exp. Ther. 2001, 296, 458-463). The relaxant effect may be the result of a reduction of Ca2+ entry through L-type Ca2+ channels (Fusi, F. et al. Br. J. Pharmacol. 2002, 137, 323-328).
To date, efforts to establish NRB as a commercially viable rodenticide have been largely unsuccessful. Over time, rats as a species have developed an evolutionary trait relating to how they sample food, particularly novel food, which reduces the risk of ingesting a potentially toxic dose. This survival strategy is most likely a consequence of their lack of an emetic centre and, therefore, their incapacity to vomit. As an acute poison, NRB has a rapid onset of action. Toxic symptoms appear almost immediately. Rats appear to develop a learnt aversion to this poison following the consumption of sub-lethal doses during sampling, a phenomenon referred to as bait-shyness (Kusano, T. J. Fac. Agri. Tottori Univ. 1975, 5, 15-26). In addition, NRB is also known to be relatively unpalatable to rats (Greaves, J. H. J. Hygiene, 1966, 64, 275-285; Ogushi, K. and Iwao, T. Eisei Dobutsu (in Japanese), 1970, 21, 181-185; Rennison, B. D. et al. J. Hygiene, 1968, 66, 147-158).
While a pre-requisite for lethality in rats, this intrinsic vasoconstrictory activity is believed to be the most significant shortcoming of NRB as a rodenticide. The sub-lethal dosing due to the unpleasant ‘taste’ of NRB is believed to be a consequence of NRB-induced vasoconstriction of the blood vessels of the buccal cavity, a primary culprit leading to bait-shyness. Efforts to address this palatability problem using microencapsulation technologies have been made, but the rapid release of the toxicant in vivo led to bait shyness (Greaves, J. H. et al. Nature 1968, 219, 402-403; Nadian, A. and Lindblom, L. Int. J. Pharm. 2002, 242, 63-68).
There remains a need for rodenticides that avoid one or more of the aforementioned disadvantages.
It is an object of the present invention to go some way towards meeting this need; and/or to at least provide the public with a useful choice.
Other objects of the invention may become apparent from the following description which is given by way of example only.
Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date.